Multiple Sclerosis, Rituximab, Hypogammaglobulinemia, and Risk of Infections.

BACKGROUND AND OBJECTIVES: B-cell-depleting therapies increase the risk of infections and hypogammaglobulinemia. These relationships are poorly understood. The objectives of these analyses were to estimate how much of this rituximab-associated infection risk is mediated by hypogammaglobulinemia and to identify other modifiable risk factors in persons with multiple sclerosis (pwMS). METHODS: We conducted a retrospective cohort study of rituximab-treated pwMS from January 1, 2008, to December 31, 2020, in Kaiser Permanente Southern California. Cumulative rituximab dose was defined as ≤2, >2 and ≤4, or >4 g. Serious infections were defined as infections requiring or prolonging hospitalizations, and recurrent outpatient infections as seeking care for ≥3 within 12 months. Exposures, outcomes, and covariates were collected from the electronic health record. Adjusted hazard ratios (aHRs) were estimated using Andersen-Gill hazards models, and generalized estimating equations were used to examine correlates of IgG values. Cross-sectional causal mediation analyses of rituximab and hypogammaglobulinemia were conducted. RESULTS: We identified 2,482 pwMS who were treated with rituximab for a median of 2.4 years (interquartile range = 1.3-3.9). The average age at rituximab initiation was 43.0 years, 71.9% were female, 49.7% were White, non-Hispanic patients, and 29.6% had advanced disability (requiring walker or worse). Seven hundred patients (28.2%) developed recurrent outpatient infections, 155 (6.2%) developed serious infections, and only 248 (10.0%) had immunoglobulin G (IgG) < 700 mg/dL. Higher cumulative rituximab dose (>4 g) was correlated with lower IgG levels (Beta = -58.8, p < 0.0001, ref ≤2 g) and, in models mutually adjusted for hypogammaglobulinemia, both were independently associated with an increased risk of serious (>4 g, aHR = 1.56, 95% CI 1.09-2.24; IgG < 500, aHR = 2.98, 95% CI 1.56-5.72) and outpatient infections (>4 g, aHR = 1.73, 95% CI 1.44-2.06; IgG < 500 aHR = 2.06, 95% CI 1.52-2.80; ref = IgG ≥ 700). Hypogammaglobulinemia explained at most 17.9% (95% CI -47.2-119%) of serious infection risk associated with higher cumulative rituximab exposure but was not significant for outpatient infections. Other independent modifiable risk factors were advanced physical disability for serious (aHR = 5.51, 95% CI 3.71-8.18) and outpatient infections (aHR = 1.24, 95% CI 1.06-1.44) and COPD (aHR = 1.68, 95% CI 1.34-2.11) and obesity (aHR = 1.25, 95% CI 1.09-1.45) for outpatient infections. DISCUSSION: Higher cumulative rituximab doses increase the risk of infections even in this population where 90% of patients maintained normal IgG levels. Clinicians should strive to use minimally effective doses of rituximab and other B-cell-depleting therapies and consider important comorbidities to minimize risks of infections.

Frailty and Risk of Serious Infections in Patients With Rheumatoid Arthritis Treated With Biologic or Targeted-Synthetic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: It remains unknown whether frailty status portends an increased risk of adverse outcomes in patients with rheumatoid arthritis (RA) initiating biologic or targeted-synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs). The objective of our study was to evaluate the association between frailty and serious infections in a younger population of patients (<65 years old) with RA who initiated b/tsDMARDs. METHODS: Using MarketScan data, we identified new users of tumor necrosis factor inhibitors (TNFi), non-TNFi biologic DMARDs, or Janus kinase inhibitors (JAKi) between 2008 and 2019 among those with RA. Patients' baseline frailty risk score was calculated using a Claims-Based Frailty Index (≥0.2 defined as frail) 12 months prior to drug initiation. The primary outcome was time to serious infection; secondarily, we examined time-to-any infection and all-cause hospitalizations. We used Cox proportional hazards to estimate adjusted hazard ratios and 95% confidence intervals (95% CIs) and assessed the significance of interaction terms between frailty status and drug class. RESULTS: A total of 57,980 patients, mean (±SD) age 48.1 ± 10.1 were included; 48,139 (83%) started TNFi, 8,111 (14%) non-TNFi biologics, and 1,730 (3%) JAKi. Among these, 3,560 (6%) were categorized as frail. Frailty was associated with a 50% increased risk of serious infections (adjusted hazard ratio [95% CI] 1.5, 1.2-1.9) and 40% higher risk of inpatient admissions (1.4 [1.3-1.6]) compared with nonfrail patients among those who initiated TNFi. Frailty was also associated with a higher risk of any infection relative to nonfrail patients among those on TNFi (1.2 [1.1-1.3]) or non-TNFi (1.2 [1.0-1.4]) or JAKi (1.4 [1.0-2.0]). CONCLUSION: Frailty is an important predictor for the risk of adverse outcomes among patients with RA treated with biologic or targeted-synthetic DMARDs.

Infectious risk when prescribing rituximab in patients with hypogammaglobulinemia acquired in the setting of autoimmune diseases.

We conducted a single-centre retrospective cohort study in a French University Hospital between 2010 and 2018 to describe the risk of severe infectious event (SIE) within 2 years after the date of first rituximab infusion (T0) prescribed after the evidence of acquired hypogammaglobulinemia (gamma globulins [GG] ≤ 6 g/L) in the setting of autoimmune diseases (AID) other than rheumatoid arthritis. SIE occurred in 26 out of 121 included patients. Two years cumulative incidence rates were 12.7 % (95 % CI 5.1-23.9) in the multiple sclerosis/neuromyelitis optica spectrum disorder group (n = 48), 27.6 % (95 % CI 15.7-40.9) in the ANCA-associated vasculitis group (n = 48) and 30.6 % (95 % CI 13.1-50.3) in the 'other AID' group (n = 25). Median GG level at T0 was 5.3 g/l (IQR 4.1-5.6) in the 'SIE' group and 5.6 g/l (IQR 4.7-5.8) in the 'no SIE' group (p = 0.04). In regression analysis, risk of SIE increased with Charlson comorbidity index ≥ 3 (OR 2.77; 95 % CI 1.01-7.57), lung disease (OR 3.20; 95 % CI 1.27-7.99), GG < 4 g/L (OR 3.39; 95 % CI 1.02-11.19), concomitant corticosteroid therapy (OR 4.13; 95 % CI 1.63-10.44), previous cyclophosphamide exposure (OR 2.69; 95 % CI 1.10-6.61), a lymphocyte count < 1000 cells/µL (OR 2.86; 95 % CI 1.12-7.21) and absence of pneumococcal vaccination (OR 3.50; 95 % CI 1.41-8.70). These results may help to inform clinical decision when considering a treatment by rituximab in immunosuppressed AID patients with hypogammaglobulinemia.

Influence of physicians' risk perception on switching treatments between high- efficacy and non-high-efficacy disease­modifying therapies in multiple sclerosis.

BACKGROUND: The decision of initiating treatment for multiple sclerosis (MS) with a high-efficacy DMT (HE DMT) or non-high-efficacy DMT (non-HE DMT) is influenced by several factors, including risk perception of patients and physicians. OBJECTIVE: Investigate the influence of physicians' risk perception on decision-making when switching treatments for MS and the reasons for switching. METHODS: Data were drawn from the Adelphi Real-World MS Disease-Specific Program (a retrospective survey) and analysis included people with RMS identified between 2017- 2021. RESULTS: Of 4129 patients with reasons for switch available, 3538 switched from non-HE DMT and 591 from HE DMT. Overall, 4.7% of patients were switched treatment by their physicians due to the risk of malignancies and infections including PML risk. The proportion of switches that were made due to the risk of PML were 23.9% in the HE DMT and 0.5% in the non-HE DMT groups. The top reasons for switching were relapse frequency (non-HE DMT vs HE-DMT: 26.8% vs 15.2%), lack of efficacy (20.9 vs 11.7) and increased number of MRI lesions (20.3% vs 12.4%). CONCLUSIONS: Physicians' risk perception of malignancies and infection excluding PML was not a leading factor when switching treatment. The risk of PML was a key factor, especially for switching patients from HE DMTs. In both groups, lack of efficacy was the key contributing factor for switching. Initiating the treatment with HE DMTs may potentially reduce the number of switches due to sub-optimal efficacy. These findings might help physicians to engage more in discussions with patients about the benefit/risk profile of DMTs.

Dilemma of immunosuppression and infection risk in systemic lupus erythematosus.

Patients with SLE are at high risk of various infections as evidenced by a number of studies. The main determinants of infection in SLE are disease activity, organ damage, and often inevitable medication. The molecular and cellular mechanisms underlying infection remain unclear. Impaired immunity, immunosuppressants and corticosteroids clearly increase the risk of infection, whereas some medications, such as low-dose IL-2, hydroxychloroquine and IVIG are safe in SLE patients with substantial evidence. It is important to balance the immunosuppression and infection risks in practice. This article focuses on medication-related infections in SLE and discusses the therapeutic options for the disease in clinical practice.

Infectious complications after intensive chemotherapy with CLAG-M versus 7+3 for AML and other high-grade myeloid neoplasms.

Contemporary data on infections after intensive chemotherapy for acute myeloid leukemia (AML) are scarce. Cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone ("CLAG-M") may result in higher remission rates than standard-dose cytarabine plus anthracycline ("7 + 3") but may result in more infections. We compared moderate to severe infections occurring up to 90 days after the first induction cycle for AML or other high-grade myeloid neoplasms in patients receiving CLAG-M for newly diagnosed (n = 196) or relapsed/refractory disease (n = 131) or 7 + 3 for newly diagnosed disease (n = 115). For newly diagnosed disease, microbiologically documented infections were more frequent after CLAG-M compared to 7 + 3 (adjusted rate ratio, 1.65 [95% CI, 1.06-2.58]; P = 0.03), with a cumulative incidence of 27.8% and 16.5% by day 90, respectively. Patients receiving CLAG-M for relapsed/refractory disease had the highest cumulative incidence of 50.7%. Bacterial bloodstream infections were the most frequent followed by respiratory tract infections. Among 29 patients (7%) who died, infection was a primary or contributing cause of death in 59%. These data indicate that infections continue to cause substantial morbidity in patients treated for AML, especially those treated for relapsed/refractory disease, and are more common with newer, more myelosuppressive regimens such as CLAG-M. Improved strategies for infection prevention are needed.

A preoptic neuronal population controls fever and appetite during sickness.

During infection, animals exhibit adaptive changes in physiology and behaviour aimed at increasing survival. Although many causes of infection exist, they trigger similar stereotyped symptoms such as fever, warmth-seeking, loss of appetite and fatigue1,2. Yet exactly how the nervous system alters body temperature and triggers sickness behaviours to coordinate responses to infection remains unknown. Here we identify a previously uncharacterized population of neurons in the ventral medial preoptic area (VMPO) of the hypothalamus that are activated after sickness induced by lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid. These neurons are crucial for generating a fever response and other sickness symptoms such as warmth-seeking and loss of appetite. Single-nucleus RNA-sequencing and multiplexed error-robust fluorescence in situ hybridization uncovered the identity and distribution of LPS-activated VMPO (VMPOLPS) neurons and non-neuronal cells. Gene expression and electrophysiological measurements implicate a paracrine mechanism in which the release of immune signals by non-neuronal cells during infection activates nearby VMPOLPS neurons. Finally, we show that VMPOLPS neurons exert a broad influence on the activity of brain areas associated with behavioural and homeostatic functions and are synaptically and functionally connected to circuit nodes controlling body temperature and appetite. Together, these results uncover VMPOLPS neurons as a control hub that integrates immune signals to orchestrate multiple sickness symptoms in response to infection.

Rituximab dose-dependent infection risk in rheumatoid arthritis is not mediated through circulating immunoglobulins, neutrophils or B cells.

OBJECTIVES: Rituximab (RTX) is a safe and effective treatment for RA. A dose-dependent infection risk was found in the REDO trial. Some studies associate RTX use with higher infection risks, possibly explained by low immunoglobulin levels and/or neutropenia. Additionally, a higher infection risk shortly after RTX infusion is reported. The objectives of this study were (i) to compare incidence rates of infections between doses and over time, and (ii) to assess B-cell counts, immunoglobulin levels, neutrophil counts and corticosteroid/disease modifying rheumatic drug use as mediating factors between RTX study dose and infection risk. METHODS: Post hoc analyses of the REDO trial were performed. Infection incidence rates between RTX dosing groups and between time periods were compared using Poisson regression. A step-wise mediation analysis was performed to investigate if any of the factors mentioned above act as a mediator in the observed dose-dependent difference in infection risk. RESULTS: The potential mediators that were investigated (circulating B-cell counts, immunoglobulin levels, neutrophil counts and drug use) did not explain the dose-dependent infection risk observed in the REDO trial. Additionally, a trend towards a time-dependent infection risk was found, with higher infection rates shortly after RTX infusion. CONCLUSIONS: These secondary analyses of the REDO trial confirmed the observed dose-dependent infection risk. Additionally, we found that infection risks were higher shortly after RTX infusion. However, a mediating pathway was not found.

Infectious complications of targeted drugs and biotherapies in acute leukemia. Clinical practice guidelines by the European Conference on Infections in Leukemia (ECIL), a joint venture of the European Group for Blood and Marrow Transplantation (EBMT), the European Organization for Research and Treatment of Cancer (EORTC), the International Immunocompromised Host Society (ICHS) and the European Leukemia Net (ELN).

The 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated with more recently approved immunotherapeutic agents and molecular targeted drugs for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Novel antibody based treatment approaches (inotuzumab ozogamicin, gemtuzumab ozogamicin, flotetuzumab), isocitrate dehydrogenases inhibitors (ivosidenib, enasidenib, olutasidenib), FLT3 kinase inhibitors (gilteritinib, midostaurin, quizartinib), a hedgehog inhibitor (glasdegib) as well as a BCL2 inhibitor (venetoclax) were reviewed with respect to their mode of action, their immunosuppressive potential, their current approval and the infectious complications and febrile neutropenia reported from clinical studies. Evidence-based recommendations for prevention and management of infectious complications and specific alerts regarding the potential for drug-drug interactions were developed and discussed in a plenary session with the panel of experts until consensus was reached. The set of recommendations was posted on the ECIL website for a month for comments from members of EBMT, EORTC, ICHS and ELN before final approval by the panelists. While a majority of these agents are not associated with a significantly increased risk when used as monotherapy, caution is required with combination therapy such as venetoclax plus hypomethylating agents, gemtuzumab ozogamicin plus cytotoxic drugs or midostaurin added to conventional AML chemotherapy.

Impact of an anti-infective screening and monitoring protocol together with infectious disease consultation in preventing infective adverse events in patients treated with anti-CD20/CD52 agents for multiple sclerosis.

BACKGROUND: Monoclonal antibodies have been a milestone in the treatment of multiple sclerosis (MS). Infective complications have been observed in patients on agents targeting lymphoid cells' surface antigens, namely anti-CD52 (alemtuzumab) and anti-CD20 agents (ocrelizumab and rituximab). Despite increasing emerging data, there is no standardized consensus regarding pre-treatment testing, vaccinations, and patient education before and during MS therapy or optimal infection-control strategies. METHODS: We led a retrospective/prospective real-life study to evaluate the effectiveness of a program of screening and prophylaxis for infective adverse events in patients with multiple sclerosis and related disorders treated with drugs directed against CD20/52 antigens. All patients referring to the MS Clinical Care and Research Center, University of Naples "Federico II", who started on alemtuzumab, ocrelizumab or rituximab (off-label use) from 1 November 2015 to 30 June 2019 were recruited. From the 1st of February 2018 patients underwent a microbiological screening and were evaluated by an infectious disease specialist (IDs) before monoclonal antibodies infusion to rule out active infections. We evaluated incidence of infective complications and predictors before (retrospectively)and after (prospectively) the introduction of the above-mentioned anti-infective program. RESULTS: We enrolled 275 patients, 104 retrospectively (pre-intervention group, PRE) and 171 prospectively (post-intervention group, POST). In PRE group, most patients were treated with alemtuzumab (58% vs 32%, p < 0.001), were more frequently DMT naïve (48% vs 36%, p = 0.044) or had received fingolimod in the past (48% vs 28%, p = 0.044) and the follow-up period was longer than in POST group (750 vs 191 days, p < 0.001). In POST group, patients were older (median age 47 vs 42 years, p = 0.030) and mostly received OCR (54% vs 14%, p < 0.001). Lymphopenia at baseline was significantly more commonly observed in PRE arm (47% vs 8%, p < 0.001). A total of 39 patients (38%) in PRE arm and 42 patients (25% in POST) group experienced one or more infections (p = 0.022); severe infections were significantly more common in PRE patients (23% vs 14%, p = 0.022). Our anti-infective program was associated with a lower IAE incidence both at univariate and multivariate analysis (aHR of infective events in PRE group: 3.652 [CI: 9.03-94.19], p < 0.001). Moreover, DMT naïve patients significantly experienced fewer infective complications (aHR: 0.470, [CI: 1.02-2.55], p = 0.040). CONCLUSIONS: A risk mitigation program including infectious disease consultation and standardized screening and prophylactic protocols was effective in reducing infective adverse events in patients receiving anti CD20/CD52 agents for MS.

Serious infections in patients with rheumatoid arthritis and psoriatic arthritis treated with tumour necrosis factor inhibitors: data from register linkage of the NOR-DMARD study.

OBJECTIVES: To estimate the incidence of serious infections (SIs) in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with tumour necrosis factor inhibitor (TNFi), and compare risk of SIs between patients with RA and PsA. METHODS: We included patients with RA and PsA from the NORwegian-Disease Modifying Anti-Rheumatic Drug registry starting TNFi treatment. Crude incidence rates (IRs) and IR ratio for SIs were calculated. The risk of SIs in patients with RA and PsA was compared using adjusted Cox-regression models. RESULTS: A total of 3169 TNFi treatment courses (RA/PsA: 1778/1391) were identified in 2359 patients. Patients with RA were significantly older with more extensive use of co-medication. The crude IRs for SIs were 4.17 (95% CI 3.52 to 4.95) in patients with RA and 2.16 (95% CI 1.66 to 2.81) in patients with PsA. Compared with the patients with RA, patients with PsA had a lower risk of SIs (HR 0.59, 95% CI 0.41 to 0.85, p=0.004) in complete set analysis. The reduced risk in PsA versus RA remained significant after multiple adjustments and consistent across strata based on age, gender and disease status. CONCLUSIONS: Compared with patients with RA, the risk of SIs was significantly lower in patients with PsA during TNFi exposure.

Hydroxymethylnitrofurazone (NFOH) decreases parasitaemia, parasitism and tissue lesion caused by infection with the Bolivia Trypanosoma cruzi type I strain in Swiss and C57BL/6 mice

Abstract The chemical hydroxymethylation of the antimicrobial nitrofurazone leads to the prodrug NFOH, also increases the anti-T. cruzi activities (in vitro and in vivo), as well as showed non-genotoxic (Ames and micronucleus assays). In the present study, we assessed the anti-T. cruzi effect of the NFOH In vivo - in acute Swiss and C57Bl/6 experimental Chagas models. The treatment started at 5 days post-infection during 20 consecutive days (orally, once day, 150mg/kg), and the parasitaemia as well as histopathology analysis were performed. In both experimental murine models, NFOH was able to reduce parasitemia blood avoiding parasitic reactivation, during immunosuppression period (dexamethasone 5mg/kg, 14 days), in 100% of the mice, and decrease tissue parasite nests, demonstrating absence of amastigote forms in all organs (100%) analyzed, data similar to benznidazole (BZN). Therefore, the results shown here pointing to the NFOH as promising compound for further preclinical studies, being a high potential drug to effective and safe chemotherapy to Chagas disease.

Efficacy and safety of ixazomib maintenance therapy for patients with multiple myeloma: a meta-analysis.

OBJECTIVES: Multiple myeloma(MM) is a malignant plasma cell disease. Maintenance treatment is beneficial to prolong survival time in patients with MM. Ixazomib was approved for the treatment of relapsed or refractory MM in combination with lenalidomide and dexamethasone. Here, we carried out a meta-analysis to determine the efficacy and safety of ixazomib maintenance therapy. METHODS: Several databases were searched including PubMed, Web of Science, Embase, the Cochrane Library, etc. The last search dated back to July, 2020. Three clinical trials with a total of 1440 participants with newly diagnosed MM were included. RESULTS AND CONCLUSION: The pooled HR of progression-free survival (PFS) was 0.69 (95% CI = 0.59-0.79), which suggested ixazomib maintenance therapy could prolong PFS remarkably. In addition, ixazomib was effective in deepening remission (RR = 1.57, 95% CI = 1.26-1.96). But it could not significantly prolong PFS in cytogenetic high-risk patients (HR = 0.74, 95% CI = 0.47-1.00). In terms of adverse reactions, our analysis revealed higher incidences of grade 3-4 thrombocytopenia (RR = 7.47, 95% CI = 2.06-27.06), neuropathy (RR = 1.48, 95% CI = 1.14-1.92), grade 3-4 infections (RR = 1.77, 95% CI = 1.21-2.59) and gastrointestinal disorders (RR = 1.48, 95% CI = 1.32-1.66). There was no significant correlation between the use of ixazomib and grade 3-4 neutropenia (RR = 1.46, 95% CI = 0.77-2.78, p = 0.25) or the occurrence of new primary malignant tumor (RR = 0.88, 95% CI = 0.53-1.46, p = 0.62). Additionally, more RCTs are needed for better choice of treatment regimen.

Risk of Infection Associated With Administration of Intravenous Iron: A Systematic Review and Meta-analysis.

Importance: Intravenous iron is recommended by many clinical guidelines based largely on its effectiveness in reducing anemia. However, the association with important safety outcomes, such as infection, remains uncertain. Objective: To examine the risk of infection associated with intravenous iron compared with oral iron or no iron. Data Sources: Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials (RCTs) from 1966 to January 31, 2021. Ongoing trials were sought from ClinicalTrials.gov, CENTRAL, and the World Health Organization International Clinical Trials Search Registry Platform. Study Selection: Pairs of reviewers identified RCTs that compared intravenous iron with oral iron or no iron across all patient populations, excluding healthy volunteers. Nonrandomized studies published since January 1, 2007, were also included. A total of 312 full-text articles were assessed for eligibility. Data Extraction and Synthesis: Data extraction and risk of bias assessments were performed according to the Preferred Reporting Items of Systematic Reviews and Meta-analyses (PRISMA) and Cochrane recommendations, and the quality of evidence was assessed using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach. Two reviewers extracted data independently. A random-effects model was used to synthesize data from RCTs. A narrative synthesis was performed to characterize the reporting of infection. Main Outcomes and Measures: The primary outcome was risk of infection. Secondary outcomes included mortality, hospital length of stay, and changes in hemoglobin and red blood cell transfusion requirements. Measures of association were reported as risk ratios (RRs) or mean differences. Results: A total of 154 RCTs (32 920 participants) were included in the main analysis. Intravenous iron was associated with an increased risk of infection when compared with oral iron or no iron (RR, 1.17; 95% CI, 1.04-1.31; I2 = 37%; moderate certainty of evidence). Intravenous iron also was associated with an increase in hemoglobin (mean difference, 0.57 g/dL; 95% CI, 0.50-0.64 g/dL; I2 = 94%) and a reduction in the risk of requiring a red blood cell transfusion (RR, 0.93; 95% CI, 0.76-0.89; I2 = 15%) when compared with oral iron or no iron. There was no evidence of an effect on mortality or hospital length of stay. Conclusions and Relevance: In this large systematic review and meta-analysis, intravenous iron was associated with an increased risk of infection. Well-designed studies, using standardized definitions of infection, are required to understand the balance between this risk and the potential benefits.

Secondary Immunodeficiency and Risk of Infection Following Immune Therapies in Neurology.

Secondary immunodeficiencies (SIDs) are acquired conditions that may occur as sequelae of immune therapy. In recent years a number of disease-modifying therapies (DMTs) has been approved for multiple sclerosis and related disorders such as neuromyelitis optica spectrum disorders, some of which are frequently also used in- or off-label to treat conditions such as chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis, myositis, and encephalitis. In this review, we focus on currently available immune therapeutics in neurology to explore their specific modes of action that might contribute to SID, with particular emphasis on their potential to induce secondary antibody deficiency. Considering evidence from clinical trials as well as long-term observational studies related to the patients' immune status and risks of severe infections, we delineate long-term anti-CD20 therapy, with the greatest data availability for rituximab, as a major risk factor for the development of SID, particularly through secondary antibody deficiency. Alemtuzumab and cladribine have relevant effects on circulating B-cell counts; however, evidence for SID mediated by antibody deficiency appears limited and urgently warrants further systematic evaluation. To date, there has been no evidence suggesting that treatment with fingolimod, dimethyl fumarate, or natalizumab leads to antibody deficiency. Risk factors predisposing to development of SID include duration of therapy, increasing age, and pre-existing low immunoglobulin (Ig) levels. Prevention strategies of SID comprise awareness of risk factors, individualized treatment protocols, and vaccination concepts. Immune supplementation employing Ig replacement therapy might reduce morbidity and mortality associated with SIDs in neurological conditions. In light of the broad range of existing and emerging therapies, the potential for SID warrants urgent consideration among neurologists and other healthcare professionals.

The risk of serious infection in rheumatoid arthritis patients receiving tocilizumab compared with tumor necrosis factor inhibitors in Korea.

OBJECTIVES: To examine the risk of serious infections (SIs) among patients with rheumatoid arthritis (RA) treated with tocilizumab compared with tumor necrosis factor inhibitor (TNFi) in Korea. METHODS: We conducted a retrospective cohort study using the Korean National Health Insurance data. The study cohort included patients ≥18 years with RA who were initiated with tocilizumab or TNFi between January 2013 and June 2018. The primary outcome was a composite endpoint of SIs, defined as an infection resulting in intravenous antimicrobial therapy or hospitalization. Secondary outcomes were organ-specific SIs. To control for confounders, we used inverse probability of treatment weighting (IPTW) using propensity score. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using a multivariable Cox regression model. RESULTS: A total of 8794 patients were identified: 1395 and 7399 patients initiated with tocilizumab and TNFi, respectively. The mean follow-up durations were 1.2 years for tocilizumab initiators and 1.0 year for TNFi initiators. After IPTW and adjustment, no increased risk of SIs was observed in tocilizumab versus TNFi (HR, 1.00; 95%CI, 0.90-1.11). In the secondary analysis, tocilizumab was associated with a higher risk of skin and subcutaneous tissue infections (HR, 1.26; 95%CI, 1.02-1.54) and a lower risk of urological and gynecological infections (HR, 0.65; 95%CI, 0.49-0.87) compared to TNFi. CONCLUSION: In this population-based cohort of RA patients in Korea, tocilizumab was not associated with a higher risk of SI compared to TNFi. However, tocilizumab should be carefully used for patients at high risk for skin-related infections.

Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202.

Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AEsc) to compare AEs, calculated for each patient by summing over products of reporting period length and grade for each all-cause grade 1-4 AE and dividing by the length of time over which AEs are assessed. A total of 176 patients received BR and 361 ibrutinib alone or with six cycles of rituximab. At 38 months median follow-up, 64% remained on ibrutinib. Median AEsc was higher with BR versus ibrutinib in the first six cycles (7.2 versus 4.9, p < 0.0001). Within ibrutinib arms, median AEsc decreased significantly to 3.7 after six cycles (p < 0.0001). 10% and 14% of BR and ibrutinib patients discontinued treatment for AEs. In ibrutinib arms, cumulative incidence of grade 3 or higher atrial fibrillation, hypertension, and infection (AEs of clinical interest) at 12 months was 4.5%, 17.5%, and 12.8%, respectively, and increased more slowly thereafter to 7.7%, 25.4%, and 20.5% at 36 months. Analytical tools including the AEsc and cumulative incidence of AEs can help to better characterize AE burden over time. ClinicalTrials.gov identifier: NCT01886872.

Rituximab exhibits a better safety profile when used as a first line of treatment for pemphigus vulgaris: A retrospective study.

BACKGROUND: Pemphigus is an autoimmune disease that is challenging to treat and has few available therapeutic options. Recently, several studies have demonstrated that rituximab may be an efficacious first-line treatment in newest guidelines. AIM: To compare the side effect profiles of rituximab administered after a course of immunosuppressant agents versus as a first-line therapy and evaluate the impact of patient characteristics and disease severity indices on occurrence of adverse effects. METHODS: A retrospective cross-sectional study was conducted on 999 patients with pemphigus vulgaris who received rituximab either as a first-line treatment or after conventional adjuvant therapies. The occurrence of partial or complete remission as well as the incidence of drug-related adverse effects were evaluated and compared between the two groups. RESULTS: Smoking, pulmonary comorbidity, and mucocutaneous phenotype were associated with an increased risk of developing infectious complications by 12.49, 5.79, and 2.37 fold, respectively. These associations were more prominent among those who received rituximab after immunosuppressant agents. CONCLUSIONS: Early use of rituximab benefits pemphigus patients, especially those with a mucocutaneous phenotype, pulmonary comorbidity, or history of smoking, and reduces their risk of infectious adverse events.

Use of granulocyte transfusion in early period in life-threatening infections of pediatric hematology and oncology patients: A single-center experience.

Despite all the developments in medicine, infections continue to be one of the most important causes of mortality in pediatric hematology and oncology patients. The more severe the degree of neutropenia develops after intensive chemotherapy in cancer patients, and the longer the neutropenia duration, the higher the risk of infection. Granulocyte transfusion (GT) is used as supportive therapy in cases where the bone marrow needs time to recover in invasive bacterial or fungal infections along with severe neutropenia. The patients who had granulocyte transfusions in our clinic between June 2019 and June 2020 were reviewed retrospectively. A total of 15 units of granulocyte concentrate were used in 11 febrile neutropenia attacks of 9 patients. The demographic characteristics of the patients and features belonging to the period of GT were recorded. In our study, the clinical response rate after GT was 90.9 %, while the hematological response rate was 40 %. Most of the patients were treated succesfully, the mortality rate was 9%. We think that the most critical factor for success with GTs is determining the neutropenic patient in particular with a combination of high-risk malignancy and acute life-threatening infection for using GT. Also, early use of GT in those patients who do not recover despite appropriate antimicrobial and supportive treatment may contribute to improvement of the clinical conditon in a shorter period of time and reduction of repeated GTs.